Minguet Susana, Huber Michael, Rosenkranz Lisa, Schamel Wolfgang W A, Reth Michael, Brummer Tilman
Department of Molecular Immunology, Institute for Biology III, Albert Ludwigs University of Freiburg and Max Planck Institute for Immunobiology, 79108 Freiburg, Germany.
Eur J Immunol. 2005 Jan;35(1):31-41. doi: 10.1002/eji.200425524.
Anergic B lymphocytes exert compromised signal transduction towards the activation of NF-kappa B in response to B cell antigen receptor (BCR) triggering, whereas activation of the ERK pathway appears normal. How this differential down-regulation of the NF-kappa B pathway is regulated remains still elusive. Here, we demonstrate that stimuli known to enhance 3',5'-cyclic adenosine monophosphate (cAMP) are capable of selectively suppressing the activation both of NF-kappa B downstream of the BCR and Toll-like receptor 4 in splenic B lymphocytes and of the high-affinity receptor for IgE in BM-derived mast cells. This suppression is accomplished by blocking phosphorylation and subsequent degradation of the inhibitor of NF-kappa B. A cAMP-dependent protein kinase (PKA) inhibitor reverses this suppressive effect, indicating that PKA is a downstream effector of cAMP in this process. Importantly, not only drugs that artificially elevate intracellular cAMP levels, but also the nucleoside adenosine, which is known to be a mediator of cellular distress, inhibit the NF-kappa B pathway. This suggests that adenosine-mediated signals represent an important step in the molecular decision process controlling inflammation versus anergic immune responses.
无反应性B淋巴细胞在B细胞抗原受体（BCR）触发时，向NF-κB激活的信号转导受损，而细胞外调节蛋白激酶（ERK）途径的激活似乎正常。NF-κB途径这种差异性下调是如何被调控的仍不清楚。在此，我们证明已知可增强3',5'-环磷酸腺苷（cAMP）的刺激能够选择性抑制脾B淋巴细胞中BCR下游的NF-κB以及Toll样受体4的激活，以及骨髓来源肥大细胞中IgE高亲和力受体的激活。这种抑制是通过阻断NF-κB抑制剂的磷酸化及随后的降解来实现的。一种cAMP依赖性蛋白激酶（PKA）抑制剂可逆转这种抑制作用，表明PKA在此过程中是cAMP的下游效应器。重要的是，不仅人工提高细胞内cAMP水平的药物，而且已知作为细胞应激介质的核苷腺苷，也能抑制NF-κB途径。这表明腺苷介导的信号是控制炎症与无反应性免疫反应的分子决策过程中的重要一步。
